BRAF Mutations in Melanoma

Melanoma is a type of skin cancer that develops from melanocytes, the cells that give skin its color. BRAF testing is one of the most important biomarker tests performed on melanoma because the result can determine whether a group of targeted medicines is an option. A “biomarker” is a measurable feature of cancer, such as a change in a gene, that provides doctors with information they cannot get from looking at cells under the microscope alone. In melanoma, the gene most often tested is BRAF, and a specific change (mutation) in this gene, called BRAF V600, makes the cancer sensitive to drugs known as BRAF and MEK inhibitors.

This article will help you understand what a BRAF result on your pathology report means, why the test is done, how it is performed, and how the result may guide treatment decisions. Finding a BRAF mutation does not change what type of cancer you have, and it is not an inherited change passed down in families. It is a change that happened within the tumor itself, and its main importance is that it opens up specific treatment options.

What is BRAF?

BRAF is a gene that gives cells the instructions to make a protein, also called BRAF, that helps control when a cell grows and divides. The BRAF protein is part of a signaling cascade inside the cell known as the MAPK pathway (sometimes written as the RAS-RAF-MEK-ERK pathway). You can think of this pathway as a relay that passes a “grow and divide” message from the cell’s surface to its control center. Normally this relay is switched on only when the cell receives the right signal, and it switches off again afterward.

A mutation in the BRAF gene can change the shape of the BRAF protein so that the relay is stuck in the “on” position. When this happens, the cell receives a constant grow-and-divide message even when it should not, and this drives the uncontrolled growth that defines cancer. The most common BRAF mutation in melanoma changes a single building block of the protein at a position called V600, almost always replacing the normal amino acid (valine) with a different one (most often glutamic acid). This specific change is written as BRAF V600E. A less common variant, in which valine is replaced by lysine, is written as BRAF V600K. Together, V600E and V600K account for the large majority of BRAF mutations found in melanoma.

Why is BRAF testing done in melanoma?

BRAF testing in melanoma is done because a mutation in the BRAF gene predicts whether the cancer is likely to respond to targeted medicines called BRAF and MEK inhibitors. These drugs are designed to block the overactive BRAF protein and the next protein in the same relay (MEK), switching off the grow-and-divide signal that the mutation keeps turned on. Because these medicines only work when the specific BRAF V600 mutation is present, the test is used to decide whether they are an option.

BRAF mutations are found in roughly 40 to 50 percent of melanomas that arise on skin that is not chronically sun-damaged. They are much less common in melanomas that begin elsewhere, such as on the palms and soles or under the nails (acral melanoma), on mucous membranes (mucosal melanoma), or inside the eye (uveal melanoma). Knowing the BRAF status helps the treatment team determine whether targeted therapy is part of the plan, alongside other systemic options such as immunotherapy.

Testing is most important when melanoma has spread beyond the original site, either to nearby lymph nodes or to distant organs (metastasis), because this is the setting in which BRAF-targeted drugs are used. For this reason, BRAF testing is usually performed for melanomas that are higher stage or that have already spread. It is generally not necessary for a thin, early melanoma that has been completely removed and has no evidence of spread, because targeted drug therapy would not be considered at that stage.

How is BRAF testing performed?

BRAF testing in melanoma looks for a mutation in the BRAF gene, most notably the BRAF V600E change, which predicts response to targeted therapy. The test is performed on a sample of the tumor that has already been removed, so it does not usually require an additional procedure. The same tissue taken at the time of biopsy or surgery, stored as a paraffin block, is used. Several laboratory methods can detect a BRAF mutation, and the choice depends on the laboratory.

Molecular methods (PCR and next-generation sequencing) — These tests read the genetic code of the BRAF gene directly to find a mutation. Polymerase chain reaction (PCR)- based tests are designed to detect specific common mutations, such as V600E and V600K. Next-generation sequencing (NGS) can simultaneously assess many genes and detect both common and less common BRAF mutations, while also providing information about other genes that may be relevant. Molecular methods are considered the most complete way to determine BRAF status.
Immunohistochemistry (IHC) — This method uses a special antibody that recognizes the abnormal protein produced specifically by the BRAF V600E mutation. It is performed on a thin slice of the tumor on a glass slide and is fast and inexpensive. A positive result strongly suggests a V600E mutation, but IHC does not detect V600K or other non-V600E mutations. For this reason, an IHC result is often confirmed by a molecular test, and a negative IHC result in a melanoma that needs treatment is usually followed by molecular testing to ensure no mutation has been missed.

How are BRAF results reported?

BRAF results in melanoma indicate whether a mutation was found in the BRAF gene, which predicts response to BRAF and MEK inhibitor therapy. Your report will describe the result in one of the following ways, and the specific wording depends on the testing method used.

BRAF mutation detected (positive) — A mutation was found in the BRAF gene. The report will usually name the specific mutation, most often “BRAF V600E” or “BRAF V600K.” This is the result that indicates the cancer may respond to BRAF-targeted therapy.
No BRAF mutation detected (wild-type or negative) — No mutation was found in the part of the BRAF gene that was tested. The report may use the term “wild-type,” which simply means the normal, unmutated form of the gene. This result indicates that BRAF-targeted drugs are not expected to work, and the treatment team will focus on other options such as immunotherapy.
BRAF V600E positive by immunohistochemistry — When the result comes from the antibody-based (IHC) method, the report describes whether the tumor cells showed staining for the abnormal V600E protein. Because IHC does not detect V600K or rarer mutations, a negative IHC result is often confirmed with a molecular test before concluding that no mutation is present.
Non-V600 BRAF mutation — Occasionally a mutation is found in the BRAF gene at a location other than V600. These mutations behave differently and do not reliably respond to the standard BRAF inhibitors used for V600 mutations. The report will specify the exact mutation so the treatment team can interpret it correctly.

What does a BRAF result mean for treatment?

The BRAF result in melanoma tells the treatment team whether the cancer carries the BRAF V600 mutation that predicts response to a group of targeted medicines called BRAF and MEK inhibitors. This information is most relevant when melanoma has spread to lymph nodes or to distant organs, because that is the setting in which these drugs are used. The pathology report does not prescribe treatment; rather, the BRAF result is one of several findings the team weighs together when discussing options with the patient.

When a BRAF V600 mutation is present, targeted therapy with a BRAF inhibitor in combination with a MEK inhibitor is a treatment option. These medicines are taken as pills and work by blocking the overactive grow-and-divide signal that the mutation keeps switched on. Approved combinations include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib. They are given as a pair rather than alone because combining a BRAF inhibitor with a MEK inhibitor works better and delays the cancer’s ability to become resistant. In some situations, BRAF-targeted therapy may also be considered after surgery (adjuvant therapy) to lower the risk that the melanoma will return.

When no BRAF mutation is present, BRAF-targeted drugs are unlikely to be effective, and the team will focus on other systemic options. The most important of these is immunotherapy, which helps the immune system recognize and attack the cancer. Immunotherapy is an option regardless of BRAF status, so a melanoma without a BRAF mutation still has effective treatment pathways available. The choice between immunotherapy and targeted therapy, and the order in which they may be used, is a decision made by the medical oncology team together with the patient, based on the full clinical picture.

Is a BRAF mutation inherited?

The BRAF mutation found in melanoma is not inherited and is not passed down to children. It is a “somatic” mutation, meaning it developed within the melanoma cells during a person’s lifetime, most often as a result of damage from ultraviolet (UV) light. Because the mutation is present only in the tumor and not in the body’s other cells, it does not appear in a blood test for inherited cancer risk and does not have implications for family members. This is an important difference from some other cancer biomarkers, such as BRCA1 and BRCA2, which can be inherited. A BRAF result on a melanoma pathology report is purely about guiding treatment for the cancer that is already present.

What happens after BRAF testing?

Once BRAF testing is complete, the result becomes part of the information the treatment team uses to plan care for the melanoma. BRAF status is considered alongside the stage of the cancer, whether it has spread to lymph nodes or distant organs, and the patient’s overall health. For a melanoma that has spread, a BRAF V600 mutation indicates that targeted therapy with a BRAF and MEK inhibitor combination may be considered, while the absence of a mutation directs attention toward immunotherapy and other approaches.

Melanoma care usually involves a multidisciplinary team that may include a medical oncologist, a surgeon, a radiation oncologist, a dermatologist, and a pathologist. The medical oncologist typically leads decisions about systemic therapy, including whether targeted therapy or immunotherapy is the better fit. If targeted therapy is started, patients are monitored for side effects and for signs that the cancer is responding. Over time, some melanomas that initially respond to BRAF-targeted therapy can develop resistance, meaning the drugs stop working as well; when this happens, the team reassesses and considers other options. Regular imaging and follow-up visits are used to track how the cancer is responding throughout treatment.

Questions to ask your doctor

Was my melanoma tested for a BRAF mutation, and what was the result?
If a mutation was found, was it a V600E, a V600K, or another type?
What method was used to test my BRAF status, and was the result confirmed by more than one method?
Does my BRAF result mean that targeted therapy is an option for me?
How does my BRAF result fit together with the stage of my melanoma?
If I have a BRAF mutation, would you consider targeted therapy, immunotherapy, or both, and in what order?
What are the possible side effects of BRAF and MEK inhibitor therapy?
If no BRAF mutation was found, what treatment options are available to me?
Does my BRAF result have any meaning for my family members?
How will we know if the treatment is working, and what happens if the cancer becomes resistant?